WO2016026445A1 - 作为fgfr激酶抑制剂的吲唑类化合物及其制备和应用 - Google Patents
作为fgfr激酶抑制剂的吲唑类化合物及其制备和应用 Download PDFInfo
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- WO2016026445A1 WO2016026445A1 PCT/CN2015/087556 CN2015087556W WO2016026445A1 WO 2016026445 A1 WO2016026445 A1 WO 2016026445A1 CN 2015087556 W CN2015087556 W CN 2015087556W WO 2016026445 A1 WO2016026445 A1 WO 2016026445A1
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Classifications
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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- C—CHEMISTRY; METALLURGY
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
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- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
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- C—CHEMISTRY; METALLURGY
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Definitions
- the present invention belongs to the field of medicine, and in particular, the present invention relates to a carbazole compound as an FGFR kinase inhibitor, and to the preparation and use thereof.
- Receptor tyrosine kinase plays a key role in tumor development, invasion and metastasis, drug resistance and other aspects due to its abnormal expression activation or gene mutation. Has become an important target for the development of anti-tumor drugs.
- fibroblast growth factor receptors FGFRs
- FGFs Fibroblast Growth Factors Due to gene amplification, mutation, fusion or ligand induction, FGFR members continue to activate, induce tumor cell proliferation, invasion, migration, promote angiogenesis, and promote tumor development.
- FGFRs are highly expressed and abnormally activated in a variety of tumors, and are closely related to the poor prognosis of cancer patients, such as non-small cell lung cancer, breast cancer, stomach cancer, bladder cancer, endometrial cancer, prostate cancer, cervical cancer, colon cancer, esophageal cancer. , keratinoma, myeloma, rhabdomyosarcoma, etc.
- cancer patients such as non-small cell lung cancer, breast cancer, stomach cancer, bladder cancer, endometrial cancer, prostate cancer, cervical cancer, colon cancer, esophageal cancer.
- keratinoma myeloma
- rhabdomyosarcoma etc.
- Studies have shown that FGFR1 amplification accounts for 20% of non-small cell lung cancer squamous cell carcinoma, and studies on proliferation and signaling pathways of FGFR1-expanded lung cancer cell lines show that FGFR selective inhibitors can effectively inhibit the activation of FGFR1 signaling pathway.
- the expansion of the chromosome (8p11–12) region in which FGFR1 is located accounts for approximately 10% of ER-positive patients, and its high expression of FGFR1 mRNA and poor prognosis of patients are associated with FGFR2 gene amplification or mutation leading to FGFR2 signaling.
- Abnormal activation of the pathway is mainly associated with gastric cancer, triple-negative breast cancer, and endometrial cancer.
- the expansion rate of FGFR2 in gastric cancer tissues is 5%-10%.
- FGFR2 amplification accounts for 4% of refractory triple negative breast cancer.
- Endometrial cancer is a common gynaecological genital tumor, and FGFR2 mutations account for about 12% of endometrial cancer.
- FGFR3 mutations accounted for 50%-60% in non-invasive bladder cancer, and FGFR3 mutations accounted for 10%-15% in invasive bladder cancer.
- FGFR3t(4;14)(p16.3;q32) gene rearrangement accounts for 15–20% in multiple myeloma.
- FGFR and its ligand FGFs of various subtypes in liver cancer have abnormal expression and activation, such as FGFR2, FGFR3, FGFR4, FGF19, FGF2, FGF5, FGF8, FGF9 and the like.
- a number of preclinical and clinical studies have demonstrated the importance of abnormal activation of the FGF/FGFR axis in liver cancer. It should not be overlooked that abnormal activation of the FGF/FGFR axis is closely related to resistance to EGFR inhibitors, neovascular inhibitors, and endocrine therapy. Therefore, the development of targeted FGFR inhibitors has become a hot topic in the research of anti-tumor drugs.
- L is selected from the group consisting of H, tetrahydropyranyl (THP);
- Each X is independently selected from the group consisting of Cl, F, H, CN;
- W, Y, Z are each independently selected from: N or CH;
- Ring A is a 5- to 8-membered arylene group which is unsubstituted, substituted or unsubstituted, or a substituted or unsubstituted 5 to 8 membered heteroarylene group, wherein the heteroaryl group contains at least one member selected from the group consisting of a hetero atom: nitrogen, oxygen, or sulfur; a substituted or unsubstituted 3 to 12 membered saturated heterocyclic ring or carbocyclic ring, wherein the heterocyclic ring contains at least one hetero atom selected from the group consisting of nitrogen, oxygen, or sulfur;
- R is H, or a substituted or unsubstituted group selected from the group consisting of:
- M is selected from the group consisting of substituted or unsubstituted C1-C6 alkylene, substituted or unsubstituted C6-C10 arylene, substituted or unsubstituted C1-C10 heteroarylene, or M No
- substitutions means that one or more hydrogen atoms on the above group are substituted with a substituent selected from the group consisting of halogen, unsubstituted or halogenated C1-C6 alkyl, unsubstituted or halogenated C1. -C6 alkoxy, unsubstituted or halogenated C1-C6 alkoxyalkyl, unsubstituted or halogenated C3-C8 cycloalkyl, unsubstituted or halogenated C2-C6 alkylcarbonyl, unsubstituted or Halogenated C1-C6 alkylene-hydroxy, unsubstituted or C1-C6 alkyl substituted amine.
- the ring A is a heteroaryl group or a saturated heterocyclic ring selected from the group consisting of the following, or the ring A is absent:
- Q 1 , Q 2 , Q 3 , Q 4 are each independently selected from: N or CH;
- B 1 , B 2 , B 3 , B 4 are each independently selected from: N or CH.
- the ring A is a heteroaryl group or a saturated heterocyclic ring selected from the group consisting of the following, or the ring A is absent:
- R is a substituted or unsubstituted group selected from the group consisting of:
- R 1 , R 2 , R 3 , R 4 are each independently selected from the group consisting of H, halogen, C1-C6 straight or branched alkyl, halogenated C1-C6 straight or branched alkyl;
- R 5 is selected from the group consisting of H, C1-C6 straight or branched alkyl, C1-C6 straight or branched alkylcarbonyl, C1-C6 straight or branched alkylene-hydroxy, C1- C6 alkoxyalkyl, unsubstituted or alkyl substituted amine, C1-C8 cycloalkyl.
- R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 are each independently selected from the group consisting of H, C1-C6 straight or branched alkyl, C1-C6 straight or branched Alkylcarbonyl, C1-C6 straight or branched alcohol group (alkylene-hydroxy);
- G 1 , G 2 , G 3 , G 4 are each independently selected from the group consisting of H, halogen, C1-C6 straight or branched alkyl, halogenated C1-C6 straight or branched alkyl;
- G 5 is selected from the group consisting of H, C1-C6 straight or branched alkyl, C1-C6 straight or branched alkylcarbonyl, C1-C6 straight or branched alkyl-hydroxy, C1-C6 Alkoxyalkyl, unsubstituted or alkyl substituted amine, C1-C8 cycloalkyl;
- E 1 and E 2 are each independently selected from the group consisting of H, halogen, straight or branched alkyl, halogenated C1-C6 straight or branched alkyl;
- E 3 is selected from the group consisting of H, C1-C6 linear alkyl or branched alkyl, C1-C6 straight or branched alkylcarbonyl, C1-C6 straight or branched alkylene-hydroxy, a C1-C6 alkoxyalkyl group, an unsubstituted or alkyl-substituted amine group, a C1-C8 cycloalkyl group;
- R 13 , R 14 , R 15 and R 16 are each independently selected from the group consisting of H, C1-C6 straight or branched alkyl, C1-C6 straight or branched alkylcarbonyl, C1-C6 straight chain Or a branched alcohol group (alkylene-hydroxyl group), or R13 and R14, R15 and R16 are bonded to a carbon atom to form a 5- to 7-membered ring;
- C0-C3 alkyl is an alkylene group having no or 1-3 carbon atoms
- the C1-C6 alkyl group is an alkylene group having 1 to 6 carbon atoms.
- L is selected from the group consisting of H, tetrahydropyranyl (THP);
- Each X is independently selected from the group consisting of H, Cl, F, CN;
- W, Y, Z are each independently selected from: N or CH;
- Ring A is a substituted or unsubstituted 6-membered aryl group, or a substituted or unsubstituted 5 to 6-membered heteroaryl group, wherein the heteroaryl group contains at least one hetero atom selected from the group consisting of nitrogen and oxygen. Or sulfur;
- M is selected from the group consisting of a substituted or unsubstituted C1-C4 alkylene group, or M is absent; said substitution means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of: Halogen, unsubstituted or halogenated C1-C4 alkyl, unsubstituted or halogenated C1-C6 alkoxy, unsubstituted or halogenated C2-C6 alkoxyalkyl, unsubstituted or halogenated C3- C8 cycloalkyl, unsubstituted or halogenated C2-C4 alkylcarbonyl, unsubstituted or halogenated C1-C4 alkyl-hydroxy, unsubstituted or C1-C6 alkyl substituted amine.
- a substituent selected from the group consisting of: Halogen, unsubstituted or halogenated C1-C4 alkyl,
- Each X is independently selected from the group consisting of H, Cl, and F;
- W, Y, Z are each independently selected from: N or CH;
- Ring A is a group selected from the group consisting of: phenyl, pyrazolyl, pyridyl, thiazolyl, pyrimidine, pyrazine or piperidinyl;
- M is selected from the group consisting of a substituted or unsubstituted C1-C3 alkylene group, or M is absent;
- any one or more of the hydrogen atoms on the substituent is substituted with a substituent selected from the group consisting of halogen, unsubstituted or halogenated C1-C4 alkyl, unsubstituted or halogenated C2-C6.
- a substituent selected from the group consisting of halogen, unsubstituted or halogenated C1-C4 alkyl, unsubstituted or halogenated C2-C6.
- the compound of formula I is a compound shown in Table A below:
- L, X, W, Y, Z, Ring A or R are the corresponding groups in the specific compounds described in the examples.
- each group is as defined in claim 1.
- the reaction in the step (a), is carried out in the presence of a copper salt; preferably, the copper salt is selected from the group consisting of CuI, Cu, CuCl, Cu 2 O , CuO, Cu(OAc) 2 , CuSO 4 ⁇ 5H 2 O, Cu(acac) 2 , CuCl 2 , CuSCN, or a combination thereof.
- a copper salt is selected from the group consisting of CuI, Cu, CuCl, Cu 2 O , CuO, Cu(OAc) 2 , CuSO 4 ⁇ 5H 2 O, Cu(acac) 2 , CuCl 2 , CuSCN, or a combination thereof.
- the reaction in the step (a), is carried out in the presence of a ligand; preferably, the ligand is a bidentate amine ligand; more preferably, the The ligand is selected from the group consisting of N1, N2-dimethyl-ethylenediamine, (1R, 2R)-(-)-N, N'-dimethyl-1,2-cyclohexanediamine, or a combination thereof .
- the reaction in the step (a), is carried out in the presence of a base; preferably, the base is an inorganic base, more preferably selected from the group consisting of K 2 CO 3 K 3 PO 4 , Cs 2 CO 3 , or a combination thereof.
- the base is an inorganic base, more preferably selected from the group consisting of K 2 CO 3 K 3 PO 4 , Cs 2 CO 3 , or a combination thereof.
- the inert solvent is selected from the group consisting of toluene, dioxane, THF, DMF, or a combination thereof.
- the method further includes the steps of:
- L is selected from the group consisting of tetrahydropyranyl (THP);
- the reaction in the step (b), is carried out in the presence of an acid; preferably, the acid is selected from the group consisting of hydrochloric acid, p-toluenesulfonic acid, TFA, or combination.
- an acid preferably, the acid is selected from the group consisting of hydrochloric acid, p-toluenesulfonic acid, TFA, or combination.
- the inert solvent is selected from the group consisting of dichloromethane, methanol, ethanol, isopropanol, n-butanol, tert-butanol, isobutanol, Or a combination thereof.
- the disease associated with the FGFR activity or expression amount is a tumor, preferably a tumor selected from the group consisting of endometrial cancer, breast cancer, gastric cancer, bladder cancer, myeloma, and liver cancer.
- the FGFR kinase is selected from the group consisting of FGFR1, FGFR2, FGFR3, or a combination thereof.
- the tumor cell is a leukemia cell line; preferably a myeloid leukemia cell line; more preferably an acute myeloid leukemia cell line KG1 cell.
- a pharmaceutical composition comprising: (i) an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof; and (ii) pharmaceutically acceptable a.
- the effective amount means a therapeutically effective amount or an inhibitory effective amount, preferably 0.01 to 99.99%.
- the pharmaceutical composition is for inhibiting the activity of FGFR kinase.
- the pharmaceutical composition is for treating a disease associated with FGFR kinase activity or expression.
- a fifth aspect of the invention provides a method of inhibiting FGFR kinase activity, comprising the steps of: administering to a subject, an inhibitory effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, according to the first aspect of the invention, Or administering to the subject, an inhibitory effective amount of the pharmaceutical composition of the fourth aspect of the invention.
- the inhibition is non-therapeutic inhibition in vitro.
- an inhibitory effective amount of a compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof when administered to a subject, the inhibitory effective amount is from 0.001 to 500 nmol/L, The preferred ground is 0.01-200 nmol/L.
- a sixth aspect of the invention provides a method of treating a disease associated with FGFR kinase activity or expression, characterized in that the method comprises: administering to a subject a therapeutically effective amount of the first aspect of the invention A compound of formula I, or a pharmaceutical composition according to the fourth invention of the invention.
- the disease associated with FGFR activity or expression is a tumor, preferably selected from the group consisting of Group of tumors: endometrial cancer, breast cancer, stomach cancer, bladder cancer, myeloma, liver cancer.
- a seventh aspect of the invention provides a method of inhibiting tumor cells in vitro, the method comprising: administering an inhibitory effective amount of a compound of formula I according to the first aspect of the invention to a subject, or a fourth aspect of the invention
- the pharmaceutical composition of aspect is provided.
- the inventors have conducted long-term and intensive studies to prepare a class of compounds having the structure shown in Formula I, and have found that they have FGFR kinase inhibitory activity. And the compound can inhibit the activity of FGFR kinase activity or expression at a very low concentration (as low as ⁇ 100nmol/L), that is, an inhibitory effect on a series of FGFR kinases, and the inhibitory activity is quite excellent. Such as tumors. Based on the above findings, the inventors completed the present invention.
- C1-C6 alkyl refers to a straight or branched alkyl group having from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, A sec-butyl group, a tert-butyl group, or the like.
- C1-C6 alkylene refers to the above C1 ⁇ C6 alkyl group formed after the loss of a hydrogen atom, for example -CH 2 -, - CH 2 -CH 2 -, or the like.
- C6-C10 arylene refers to a group formed by an aryl group having 6 to 10 carbon atoms which loses a hydrogen atom, and includes a monocyclic or bicyclic arylene group such as a phenylene group, a naphthylene group, or the like. Group.
- 6-membered aryl refers to phenyl
- 5-8 membered aryl refers to a carbon-unsaturated substituent of a 5-8 membered ring, such as a phenyl group, or the like.
- 5- to 8-membered heteroaryl refers to a non-saturated ring-based substituent having a heterocyclic ring selected from O, S, N or P on a ring system having 5-8 members, such as pyridyl, Thienyl, or a similar group.
- saturated 3- to 12-membered carbocyclic ring means a saturated carbocyclic ring having 3 to 12 carbon atoms, such as a cyclohexyl group, or the like.
- 3- to 12-membered heterocyclic ring refers to a saturated ring system substituent having a hetero atom of one or more selected from O, S, N or P in a ring system having 3 to 12 members, such as piperidinyl, pyrrolyl. , or a similar group.
- halogen refers to F, Cl, Br and I.
- the terms "containing”, “comprising” or “including” mean that the various ingredients may be used together in the mixture or composition of the present invention. Therefore, the terms “consisting essentially of” and “consisting of” are encompassed by the term “contains.”
- the term "pharmaceutically acceptable” ingredient means a substance which is suitable for use in humans and/or animals without excessive adverse side effects (such as toxicity, irritation, and allergic reaction), that is, a reasonable benefit/risk ratio.
- the term "effective amount" means an amount of a therapeutic agent that treats, alleviates or prevents a target disease or condition, or an amount that exhibits a detectable therapeutic or prophylactic effect.
- the precise effective amount for a subject will depend on the size and health of the subject, the nature and extent of the condition, and the combination of therapeutic and/or therapeutic agents selected for administration. Therefore, it is useless to specify an accurate effective amount in advance. However, for a given condition, routine experimentation can be used to determine the effective amount that the clinician can determine.
- substituted means that one or more hydrogen atoms on the group are selected from Substituents of the group are substituted: halogen, unsubstituted or halogenated C1-C6 alkyl, unsubstituted or halogenated C2-C6 acyl, unsubstituted or halogenated C1-C6 alkyl-hydroxy.
- each of the chiral carbon atoms may be optionally in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.
- compound of the invention refers to a compound of formula I.
- the term also encompasses various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of formula I.
- the term "pharmaceutically acceptable salt” refers to a salt of the compound of the invention formed with an acid or base suitable for use as a medicament.
- Pharmaceutically acceptable salts include inorganic and organic salts.
- a preferred class of salts are the salts of the compounds of the invention with acids.
- Suitable acids for forming salts include, but are not limited to, mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzoic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.
- mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid,
- Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid,
- L is selected from the group consisting of H, tetrahydropyranyl (THP);
- Each X is independently selected from the group consisting of Cl, F, H, CN;
- W, Y, Z are each independently selected from: N or CH;
- Ring A is a non-, substituted or unsubstituted 5-8-membered aryl group, or a substituted or unsubstituted 5- to 8-membered heteroaryl group, wherein the heteroaryl group contains at least one hetero atom selected from the group consisting of a nitrogen, oxygen, or sulfur; a substituted or unsubstituted 3 to 12 membered saturated heterocyclic ring or carbocyclic ring, wherein said heterocyclic ring comprises at least one hetero atom selected from the group consisting of nitrogen, oxygen, or sulfur; Or
- R is H or a substituted or unsubstituted group selected from the group consisting of:
- M is selected from the group consisting of: a substituted, unsubstituted or unsubstituted C1-C6 alkylene group, a substituted or unsubstituted C6-C10 arylene group, a substituted or unsubstituted C1-C10 heteroarylene group;
- substitution means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of halogen, unsubstituted or halogenated C1-C6 alkyl, unsubstituted or halogenated C2-C6 acyl, Unsubstituted or halogenated C1-C6 alkyl-hydroxy.
- the ring A is a heteroaryl group selected from the group consisting of:
- Q 1 , Q 2 , Q 3 , Q 4 are each independently selected from: N or CH;
- B 1 , B 2 , B 3 , and B 4 are each independently selected from: N or CH.
- the ring A is a heteroaryl group selected from the group consisting of:
- R is a substituted or unsubstituted group selected from the group consisting of:
- R 1 , R 2 , R 3 , R 4 are each independently selected from the group consisting of H, halogen, C1-C6 linear alkyl or branched alkyl, halogenated C1-C6 linear alkyl or branched alkane base;
- R 5 is selected from the group consisting of H, a C1-C6 linear alkyl or branched alkyl group, a C1-C6 linear or branched acyl group, and a C1-C6 linear or branched alkylene-hydroxy group.
- R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 are each independently selected from the group consisting of H, C1-C6 linear alkyl or branched alkyl, C1-C6 straight or branched Chain acyl group, C1-C6 linear or branched alcohol group (alkylene-hydroxyl group);
- G 1 , G 2 , G 3 , G 4 are each independently selected from the group consisting of H, halogen, C1-C6 linear alkyl or branched alkyl, halogenated C1-C6 linear alkyl or branched alkane Base or
- G 5 is selected from the group consisting of H, C1-C6 linear alkyl or branched alkyl, C1-C6 straight or branched acyl, C1-C6 straight or branched alkyl-hydroxy;
- E 1 and E 2 are each independently selected from the group consisting of H, halogen, linear alkyl or branched alkyl, halogenated C1-C6 linear alkyl or branched alkyl;
- E 3 is selected from the group consisting of H, C1-C6 linear alkyl or branched alkyl, C1-C6 straight or branched acyl, C1-C6 straight or branched alkylene-hydroxy;
- R 13 , R 14 , R 15 and R 16 are each independently selected from the group consisting of H, C1-C6 linear alkyl or branched alkyl, C1-C6 straight or branched acyl, C1-C6 straight chain Or branched alcohol groups (alkylene-hydroxy);
- C0-C3 alkyl is an alkylene group having no or 1-3 carbon atoms
- the C1-C6 alkyl group is an alkylene group having 1 to 6 carbon atoms.
- L is selected from the group consisting of H, tetrahydropyranyl (THP);
- Each X is independently selected from the group consisting of H, Cl, F, CN;
- W, Y, Z are each independently selected from: N or CH;
- Ring A is a substituted or unsubstituted 6-membered aryl group, or a substituted or unsubstituted 5 to 6-membered heteroaryl group, wherein the heteroaryl group contains at least one hetero atom selected from the group consisting of nitrogen and oxygen. Or sulfur;
- M is selected from the group consisting of a substituted or unsubstituted C1-C4 alkylene group, or M is absent;
- substitution means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of halogen, unsubstituted or halogenated C1-C4 alkyl, unsubstituted or halogenated C2-C4 acyl, Unsubstituted or halogenated C1-C4 alkyl-hydroxy.
- L is H
- Each X is independently selected from the group consisting of H, Cl, and F;
- W, Y, Z are each independently selected from: N or CH;
- Ring A is a group selected from the group consisting of: phenyl, pyrazolyl, pyridyl, thiazolyl, piperidinyl;
- M is selected from the group consisting of a substituted or unsubstituted C1-C3 alkylene group, or M is absent;
- substitution means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of halogen, unsubstituted or halogenated C1-C4 alkyl, unsubstituted or halogenated C2-C4 acyl, Unsubstituted or halogenated C1-C4 alkyl-hydroxy.
- the compound of formula I is a compound selected from the group consisting of:
- each reaction is usually carried out in an inert solvent at room temperature to reflux temperature.
- the reaction time is usually from 0.1 to 60 hours, preferably from 0.5 to 48 hours.
- a preferred method of preparing a compound of formula I comprises the steps of:
- the reaction is carried out in the presence of a copper salt; preferably, the copper salt is selected from, but not limited to, the following groups: CuI, Cu, CuCl, Cu 2 O, CuO, Cu(OAc) 2 , CuSO 4 ⁇ 5H 2 O, Cu(acac) 2 , CuCl 2 , CuSCN, or a combination thereof.
- the copper salt is selected from, but not limited to, the following groups: CuI, Cu, CuCl, Cu 2 O, CuO, Cu(OAc) 2 , CuSO 4 ⁇ 5H 2 O, Cu(acac) 2 , CuCl 2 , CuSCN, or a combination thereof.
- the reaction is carried out in the presence of a ligand; preferably, the ligand is a bidentate amine ligand; more preferably, the ligand is selected from (but not limited to) The lower group: N1, N2-dimethyl-ethylenediamine, (1R, 2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine, or a combination thereof.
- the reaction is carried out in the presence of a base; preferably, the base is an inorganic base, more preferably selected from, but not limited to, the following group: K 2 CO 3 , K 3 PO 4 , Cs 2 CO 3 , or a combination thereof.
- the base is an inorganic base, more preferably selected from, but not limited to, the following group: K 2 CO 3 , K 3 PO 4 , Cs 2 CO 3 , or a combination thereof.
- the inert solvent is selected from, but not limited to, the lower group: toluene, dioxane, THF, DMF, or a combination thereof.
- the method further includes the steps of:
- the reaction is carried out in the presence of an acid; preferably, the acid is selected from, but not limited to, the lower group: hydrochloric acid, p-toluenesulfonic acid, TFA, or a combination thereof.
- an acid preferably, the acid is selected from, but not limited to, the lower group: hydrochloric acid, p-toluenesulfonic acid, TFA, or a combination thereof.
- the inert solvent is selected from, but not limited to, the following group: dichloromethane, methanol, ethanol, isopropanol, n-butanol, tert-butanol, isobutanol, or a combination thereof .
- a more preferred preparation method comprises the following steps:
- Compound A2 can be reacted with Compound A1 and DHP in an inert solvent (DCM, THF, etc.) under the catalysis of an acid such as, but not limited to, p-toluenesulfonic acid, trifluoroacetic acid.
- an inert solvent DCM, THF, etc.
- Compound A4 may be subjected to Suzuki coupling by a corresponding boronic acid or ester in an inert solvent (such as dioxane and water, toluene and water, DMSO, THF, DMF, etc.) in a catalyst (such as four ( Triphenylphosphine)palladium, tris(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3 ), bis(dibenzylideneacetone)palladium, dichlorobis(triphenylphosphine)palladium, triphenyl Palladium phosphinate, bis(tri-o-phenylmethylphosphine)palladium dichloride, 1,2-bis(diphenylphosphino)ethanepalladium dichloride, etc.) and bases (such as potassium carbonate, potassium fluoride, fluorine) Antimony, sodium fluoride, potassium phosphate, potassium hydrate hydrate, sodium carbonate, sodium hydrogencarbonate
- Compound A5 can be obtained by slowly dropping SO 2 Cl 2 from compound A4 in an inert solvent (dichloromethane, THF, acetonitrile) and stirring at room temperature.
- an inert solvent dichloromethane, THF, acetonitrile
- Compound A6 can be obtained by deprotecting compound A5, and adding an acid (such as hydrochloric acid, in an inert solvent (such as dichloromethane, methanol, ethanol, isopropanol, n-butanol, tert-butanol, isobutanol, etc.) Toluenesulfonic acid, TFA) gave compound A6.
- an acid such as hydrochloric acid
- an inert solvent such as dichloromethane, methanol, ethanol, isopropanol, n-butanol, tert-butanol, isobutanol, etc.
- Compound A7 may be added with compound A6, iodine and NaOH in an inert solvent (1,4-dioxane, DMF, etc.). Stir at room temperature.
- Compound A8 can be reacted with Compound A7 and DHP in an inert solvent (DCM, THF, etc.) under the catalysis of an acid such as, but not limited to, p-toluenesulfonic acid, trifluoroacetic acid.
- an inert solvent DCM, THF, etc.
- Compound A10 may be amidated by aromatization of compound A8 and compound A9.
- the reaction is carried out in the presence of one or more of the following: a copper salt, which may be, but not limited to, CuI, Cu, CuCl, Cu 2 O, CuO, Cu(OAc) 2 , CuSO 4 ⁇ 5H 2 O, Cu(acac) 2 , CuCl 2 , CuSCN, or a combination thereof.
- a copper salt which may be, but not limited to, CuI, Cu, CuCl, Cu 2 O, CuO, Cu(OAc) 2 , CuSO 4 ⁇ 5H 2 O, Cu(acac) 2 , CuCl 2 , CuSCN, or a combination thereof.
- a ligand which may be a bidentate amine ligand, including but not limited to N1, N2-dimethyl-ethylenediamine, (1R, 2R)-(-)-N, N'-dimethyl- 1,2-cyclohexanediamine, a base
- the base may be, but not limited to, an inorganic base such as K 2 CO 3 , K 3 PO 4 , Cs 2 CO 3
- the solvent of the reaction may be, but not limited to, toluene, Oxycyclohexane, THF, DMF.
- Compound A11 can be obtained by deprotecting compound A10 using an appropriate acid such as, but not limited to, hydrochloric acid, p-toluenesulfonic acid, TFA in an inert solvent (such as dichloromethane, methanol, ethanol, isopropanol, n-butyl)
- an inert solvent such as dichloromethane, methanol, ethanol, isopropanol, n-butyl
- Compound 11 is obtained by alcohol, tert-butanol, isobutanol or the like.
- the disease associated with the FGFR activity or expression amount is a tumor, preferably a tumor selected from the group consisting of endometrial cancer, breast cancer, gastric cancer, bladder cancer, myeloma, and liver cancer.
- the FGFR kinase is selected from the group consisting of FGFR1, FGFR2, FGFR3, or a combination thereof.
- the tumor cell is a leukemia cell line; preferably a myeloid leukemia cell line; more preferably an acute myeloid leukemia cell line KG1 cell.
- the compounds of formula I of the present invention are useful in the preparation of a pharmaceutical composition comprising: (i) an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof; and (ii) pharmaceutically acceptable a.
- the effective amount refers to a therapeutically effective amount or an inhibitory effective amount.
- the pharmaceutical composition is for inhibiting the activity of FGFR kinase.
- the pharmaceutical composition is for treating a disease associated with FGFR kinase activity or expression.
- the compounds of the formula I according to the invention may also be used in a method for inhibiting the activity of FGFR kinase, characterized by comprising the step of administering an inhibitory effective amount of a compound of the formula I according to claim 1 or a pharmaceutically acceptable salt thereof, to a subject. Or administering an inhibitory effective amount of the pharmaceutical composition of claim 7 to the subject.
- the inhibition is non-therapeutic inhibition in vitro.
- an inhibitory effective amount of a compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof when administered to a subject, the inhibitory effective amount is from 0.001 to 500 nmol/L, The preferred ground is 0.01-200 nmol/L.
- the invention also provides a method of treating a disease associated with FGFR kinase activity or expression, the method comprising: administering to a subject a therapeutically effective amount of a compound of formula I, or said compound comprising formula I as effective A pharmaceutical composition of the ingredients.
- the disease associated with the FGFR activity or expression amount is a tumor, preferably a tumor selected from the group consisting of endometrial cancer, breast cancer, gastric cancer, bladder cancer, myeloma, and liver cancer.
- the compound of the present invention has excellent inhibitory activity against FGFR kinase (Kinase) such as FGFR1, FGFR2, FGFR3, the compound of the present invention and various crystal forms thereof, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates
- a pharmaceutical composition containing the compound of the present invention as a main active ingredient can be used for the treatment, prevention, and alleviation of diseases associated with FGFR activity or expression.
- the compounds of the invention are useful in the treatment The following diseases: endometrial cancer, breast cancer, stomach cancer, bladder cancer, myeloma, liver cancer and so on.
- compositions of the present invention comprise a safe or effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
- safe and effective amount it is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
- the pharmaceutical compositions contain from 1 to 2000 mg of the compound of the invention per agent, more preferably from 5 to 200 mg of the compound of the invention per agent.
- the "one dose” is a capsule or tablet.
- “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. By “compatibility” it is meant herein that the components of the composition are capable of intermingling with the compounds of the invention and with each other without significantly reducing the efficacy of the compound.
- pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid).
- magnesium stearate magnesium stearate
- calcium sulfate vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier Wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
- the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration. .
- Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
- the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent such as paraffin; (f) Absorbing accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and
- Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compound in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. If necessary, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
- Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
- the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
- inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethyl
- compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and flavoring agents.
- adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and flavoring agents.
- the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
- suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
- compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
- Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
- Dosage forms for the compounds of the invention for topical administration include ointments, powders, patches, propellants and inhalants.
- the active ingredient is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or, if necessary, propellants.
- the compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
- a safe and effective amount of a compound of the invention is administered to a mammal (e.g., a human) in need of treatment wherein the dosage is a pharmaceutically effective effective dosage, for a 60 kg body weight
- the dose to be administered is usually from 1 to 2000 mg, preferably from 5 to 500 mg.
- specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.
- FGFR inhibitor having a novel structure and inhibiting the activity of various FGFR kinases at very low concentrations.
- a class of pharmaceutical compositions for treating diseases associated with FGFR kinase activity is provided.
- the enzyme reaction substrate Poly(Glu, Tyr) 4:1 was diluted with potassium-free PBS (10 mM sodium phosphate buffer, 150 mM NaCl, pH 7.2-7.4) to 20 ⁇ g/mL, and 125 ⁇ L/well coated with the ELISA plate. The reaction was carried out at 37 ° C for 12-16 hours. After discarding the liquid in the well, the plate was washed, and the plate was washed three times with 200 ⁇ L/well of T-PBS (PBS containing 0.1% Tween-20) for 5 minutes each time. The plate was dried in an oven at 37 ° C for 1-2 hours.
- reaction buffer 50 mM HEPES pH 7.4, 50 mM MgCl 2 , 0.5 mM MnCl 2 , 0.2 mM Na 3 VO 4 , 1 mM DTT
- the compound is diluted with DMSO to a suitable concentration, 1 ⁇ L/well or containing the corresponding concentration of DMSO (negative control well), and then added with each kinase kinase domain recombinant protein diluted with 49 ⁇ L of reaction buffer to initiate the reaction, each experiment requires ATP-free Two wells of the control well.
- the reaction was carried out for 1 hour at 37 ° C on a shaker (100 rpm).
- the plate was washed three times with T-PBS.
- One anti-PY99 dilution was added to 100 ⁇ L/well, and the reaction was shaken at 37 ° C for 0.5 hour.
- the plate was washed three times with T-PBS.
- a second anti-horseradish peroxidase-labeled goat anti-mouse IgG dilution was added at 100 ⁇ L/well, and shaken at 37 ° C for 0.5 hour.
- the plate was washed three times with T-PBS.
- the inhibition rate of the sample is obtained by the following formula:
- IC 50 values were obtained by four-parameter regression using software attached to the microplate reader.
- Some IC 50 information is provided in the table below.
- the symbol + represents an IC 50 of less than 100 nm
- the symbol ++ represents an IC 50 of 100 nm to 500 nm
- N/A represents no data.
- CCK-8 cell counting kit for growth inhibition of acute myeloid leukemia cell line KG1 cells (FGFR1 fusion protein expressed in the cytoplasm, FGFR1-dependent tumor cell line, purchased from ATCC cell bank) Detection.
- the specific steps are as follows: KG1 cells in logarithmic growth phase were inoculated into 96-well culture plates at a suitable density, 90 ⁇ L per well, and after incubation overnight, different concentrations of compounds were added for 72 hr, and a solvent control group (negative control) was set. After the compound was treated for 72h, the effect of the compound on cell proliferation was detected by CCK-8 cell counting kit (Dojindo).
- inhibition rate (%) (OD negative control well-OD administration well) / OD negative control well ⁇ 100%.
- IC 50 values were obtained by four-parameter regression using software attached to the microplate reader.
- the IC 50 values for some of the compounds are provided in the table below.
- the symbol + represents an IC 50 of less than 200 nm
- the symbol ++ represents an IC 50 of 200 nm to 1000 nm.
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ES15833329T ES2904544T3 (es) | 2014-08-19 | 2015-08-19 | Compuestos de indazol como inhibidores de la cinasa FGFR, preparación y uso de los mismos |
KR1020177007663A KR102022866B1 (ko) | 2014-08-19 | 2015-08-19 | 섬유 아세포 성장 인자 수용체 키나아제 억제제인 인다졸계 화합물 및 이의 제조와 응용 |
BR112017003312-7A BR112017003312B1 (pt) | 2014-08-19 | 2015-08-19 | Compostos de indazol como inibidores de fgfr quinase, preparação e uso dos mesmos |
US15/504,854 US10562900B2 (en) | 2014-08-19 | 2015-08-19 | Indazole compounds as FGFR kinase inhibitor, preparation and use thereof |
AU2015306561A AU2015306561B2 (en) | 2014-08-19 | 2015-08-19 | Indazole compounds as FGFR kinase inhibitor, preparation and use thereof |
CA2958503A CA2958503C (en) | 2014-08-19 | 2015-08-19 | Indazole compounds as fgfr kinase inhibitor, preparation and use thereof |
EP15833329.4A EP3184521B1 (en) | 2014-08-19 | 2015-08-19 | Indazole compounds as fgfr kinase inhibitors, preparation and use thereof |
KR1020197026420A KR102166002B1 (ko) | 2014-08-19 | 2015-08-19 | 섬유 아세포 성장 인자 수용체 키나아제 억제제인 인다졸계 화합물 및 이의 제조와 응용 |
MX2017002206A MX2017002206A (es) | 2014-08-19 | 2015-08-19 | Compuestos de indazol como inhibidores de cinasa fgfr, preparacion y uso de los mismos. |
MYPI2017000250A MY188447A (en) | 2014-08-19 | 2015-08-19 | Indazole compounds as fger kinase inhibitor, preparation and use thereof |
RU2017105781A RU2719428C2 (ru) | 2014-08-19 | 2015-08-19 | Индазольные соединения в качестве ингибиторов киназы fgfr, их получение и применение |
JP2017509744A JP6445684B2 (ja) | 2014-08-19 | 2015-08-19 | Fgfrキナーゼ阻害剤としてのインダゾール系化合物およびその製造と使用 |
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WO2016188214A1 (zh) * | 2015-05-27 | 2016-12-01 | 上海海和药物研究开发有限公司 | 一种新型激酶抑制剂的制备及其应用 |
JP2019524883A (ja) * | 2016-08-09 | 2019-09-05 | 広州諾誠健華医薬科技有限公司Guangzhou Innocare Pharma Tech Co.,Ltd. | Fgfr阻害剤としての複素環化合物 |
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KR20190105679A (ko) | 2019-09-17 |
RU2719428C2 (ru) | 2020-04-17 |
MX2017002206A (es) | 2018-01-23 |
US10562900B2 (en) | 2020-02-18 |
KR102022866B1 (ko) | 2019-09-19 |
AU2015306561B2 (en) | 2018-03-15 |
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PE20170774A1 (es) | 2017-07-04 |
RU2017105781A3 (pt) | 2019-01-21 |
CN105524048A (zh) | 2016-04-27 |
KR20170069199A (ko) | 2017-06-20 |
EP3184521A1 (en) | 2017-06-28 |
JP6445684B2 (ja) | 2018-12-26 |
CA2958503A1 (en) | 2016-02-25 |
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US20170275291A1 (en) | 2017-09-28 |
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AU2015306561A1 (en) | 2017-04-06 |
ES2904544T3 (es) | 2022-04-05 |
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